Psychiatry Research 304 (2021) 114139

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Psychiatry Research
journal homepage: www.elsevier.com/locate/psychres

Review article

Genetic markers of the stress generation model: A systematic review

Anees Bahji a, *, Evan Forth b, Tegan Hargreaves c, Kate Harkness c, d
a
Department of Psychiatry, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4, Canada
b
Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada
c
Department of Psychiatry, Queen’s University, Kingston, ON, Canada
d
Department of Psychology, Queen’s University, Kingston, ON, Canada

A R T I C L E I N F O A B S T R A C T

Keywords: Aim: Robust evidence suggests that depression, and risk for depression, are associated with the generation of
Humans stressful life events. This tendency to generate stress may be genetically determined. This systematic review
Adolescent aimed to identify specific molecular genetic markers associated with the generation of interpersonal stressful life
Young adult
events, at least in part dependent on individuals’ behavior.
Adult
Serotonin plasma membrane transport proteins
Method: We followed the PRISMA guidelines in searching six electronic databases (PubMed, MEDLINE, Psy­
Receptors cINFO, CINAHL, Cochrane, and EMBASE) from inception to January 2021, and we reviewed the reference lists of
Genetic markers eligible articles for additional records. We restricted eligibility to empirical studies involving at least one genetic
Oxytocin marker and including proximal life events. We evaluated the risk of bias using the Newcastle Ottawa Scale for
Serotonin observational studies. The outcome permitted a distinction between life events dependent on the individual’s
Polymorphism, single nucleotide agency versus independent events.
Genetic Profile Results: Seven studies, including 3585 participants, met eligibility criteria. Three were longitudinal, and four
Depression
were cross-sectional; six included adolescents and young adults, and one focused on middle adulthood. Four
Pituitary-Adrenal System
examined the serotonin-transporter-linked promoter region (5-HTTLPR), two examined the rs53576 single
Promoter Regions
Genetic nucleotide polymorphism of the oxytocin receptor gene (OXTR), and one examined a multilocus genetic profile
Molecular Biology score including four hypothalamic-pituitary-adrenal (HPA) axis genes. There were no significant direct corre­
lations between genotype and life events in any study. Instead, their relation was significantly moderated by
symptoms, exposure to early adversity, or attachment. Consistent with the stress generation hypothesis, this
moderation relation was significant in predicting exposure to dependent life events but was not significant in
predicting independent life event exposure.
Conclusions: There is evidence that genetic variation in the serotonin, HPA axis, and oxytocin systems moderates
the effects of psychosocial vulnerability markers on the generation of proximal, dependent life events. Future
research should examine additional genetic markers in systems known to confer risk for stress generation.
PROSPERO: CRD42019136886.

1. Background depression onset. Careful prospective behavioral genetic research shows

that the association between SLEs and depression is causal (Kendler
Globally, depression affects nearly 300 million people and is the et al., 1999). Exposure to life events is not random, however. A key
worldwide leading cause of morbidity (Herrman et al., 2019). Exposure driver of this vulnerability is the tendency of depression-vulnerable in­
to stressful life events (SLEs) is the strongest proximal trigger of dividuals to select themselves into high-risk environments (Kendler and

Acknowledgments: We would like to acknowledge the University of Calgary Health Sciences Librarians for their support in developing our search strategy.
Disclosure: Dr. Bahji is a recipient of the 2020 Friends of Matt Newell Endowment in Substance Abuse through the University of Calgary’s Cumming School of
Medicine.Funding Sources: none.Role of Authors: All the authors contributed to this study’s design, interpreting the data, subsequent manuscript drafts (and
revisions), and final approval for submission. Two co-authors conducted the initial systematic review (EB and AB). One author (AB) wrote the initial draft of the work
and managed revision feedback from the other authors. Finally, one co-author supervised and provided contextualized input throughout all stages of the manuscript’s
generation (KH).
* Corresponding author.
E-mail address: anees.bahji1@ucalgary.ca (A. Bahji).

https://doi.org/10.1016/j.psychres.2021.114139
Received 26 March 2021; Received in revised form 16 July 2021; Accepted 24 July 2021
Available online 26 July 2021
0165-1781/© 2021 Elsevier B.V. All rights reserved.
A. Bahji et al.
Karkowski-Shuman, 1997a). This is an example of what Plomin et al.
referred to as ‘active genotype-environment correlation,’ or the in­
dividual’s tendency to contribute to their environment actively and even
seek out environments consistent with their genotype (Plomin et al.,
1977).
A special case of active genotype-environment correlation is “stress
generation” (Hammen, 1991, 2020). The stress generation hypothesis of
depression proposes that some individuals with a history of depression,
or depressogenic vulnerabilities, may generate SLEs due, at least in part,
to maladaptive personality characteristics that may be genetically
mediated. One of the unique insights reflected in this hypothesis is that
not all environmental contexts can be generated. In particular, the stress
generation hypothesis distinguishes between SLEs that are dependent on
an individual’s characteristics or behaviors (e.g., the break-up of a
romantic relationship, getting fired from a job due to incompetence) and
those that are independent or ‘fateful’ (e.g., death of a relative by can­
cer) (Hammen, 1991). A very robust literature has provided support for
the basic tenets of the stress generation hypothesis; specifically, in­
dividuals with depression report higher prospective rates of exposure to
dependent, but not independent, life events than non-depressed groups
(Liu, 2013; Hammen, 2020). The stress generation hypothesis has sub­
sequently been extended to other clinical conditions, including bipolar
disorder and borderline personality disorder (Allen et al., 2020; Alloy
et al., 2020). Further, healthy individuals with particular risk markers
for psychopathology, such as maternal history of depression, are also at
greater risk for generating dependent stress than those without (Adrian
and Hammen, 1993).
Stress generation is an important clinical phenomenon that has
negative prognostic implications in depression. Longitudinal studies
have confirmed that stress generation contributes strongly to the chro­
nicity and recurrence of depression (Hammen et al., 2012) and is related
to inadequate response to depression treatment (Bulmash et al., 2009;
Fournier et al., 2009). Further, individuals at risk for stress generation
have shown high continuity of stress exposure over decades (Hazel et al.,
2008). This long-term stress burden imposed by stress generation has
considerable maladaptive consequences for physical and mental health
(McEwen and Morrison, 2013). Therefore, understanding the mecha­
nisms underlying the generation of stress has implications for depression
prevention (Hammen, 2020).
Using twin designs as a proxy for genetic risk, early behavioral ge­
netics research set the stage for considering genetic background as a risk
factor for stress generation. For example, using data from their sample of
over 2000 female twin pairs from the Virginia Twin Registry, Kendler
and colleagues found that lifetime history depression in the co-twin
significantly predicted odds of exposure to dependent life events in
the proband, including marital problems, divorce, job loss, and financial
problems (Kendler et al., 1993; Kendler and Karkowski-Shuman, 1997b,
1999). Moreover, these associations held even after controlling for the
proband’s own current level of depression. In contrast, the twin’s lia­
bility to depression did not predict odds of exposure to independent
events in the proband, including deaths or illnesses of others, or being
the victim of a robbery or other crime (Kendler et al., 1993, 1999).
However, only very recently have studies begun to examine which
particular set of molecular genetic markers drive associations with
dependent versus independent SLEs.
For the past 20 years, molecular genetics research incorporating SLEs
has focused on predicting depression as the outcome from an interaction
of molecular genetic markers and distal (e.g., childhood maltreatment)
or proximal (e.g., past-year SLEs) stress exposure. Early GxE work in
depression focused specifically on a polymorphism in the promoter re­
gion of the serotonin transporter gene (5-HTTLPR). Several studies re­
ported that individuals homozygous or heterozygous for the short (S)
allele of the 5-HTTLPR—showing less transcriptional activity and lower
serotonin uptake—had a greater risk for depression than those homo­
zygous for the long (L) allele, but only in the context of stress exposure
(Heils et al., 1996; Caspi et al., 2003). However, this work was
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Psychiatry Research 304 (2021) 114139
subsequently criticized following several failures to replicate and the
inability to detect robust effects through meta-analysis (Risch et al.,
2009). Thus, while this research question has been revitalized somewhat
by examining profile risk scores and using Genome-Wide Association
Study (GWAS) designs, there is generally dampened enthusiasm for
molecular genetics studies that predict depression outcomes in the face
of stress due to a failure to replicate effects.
Far fewer molecular genetic studies exist examining SLE exposure
itself as the outcome, and even fewer have examined the genetic markers
involved in the generation of dependent SLEs, specifically. However, it is
important to note that this latter design may be more powerful than the
former for several reasons. First, depression is a very heterogeneous
outcome with considerable variability in syndromal presentation, eti­
ology, and pathology (Buch and Liston, 2021). In contrast, the genera­
tion of dependent life events may represent a more homogenous and
transdiagnostic intermediate phenotype. Second, as noted above, the
literature supports the basic stress generation phenomenon and supports
proxies of genetic vulnerability (e.g., family history, twin designs) as a
robust correlate. Finally, the generation of dependent stress is predicted
by characteristics known to have a strong genetic basis (e.g., neuroti­
cism) (Kushner et al., 2017).
Likely as a result of the large body of literature focusing on the 5-
HTTLPR in molecular genetic work in depression, this marker has also
received the most attention in the studies reviewed below examining
stress generation as the outcome. Genetic markers in two additional
neurobiological systems have also been targeted. First, variations in
genes that regulate the function of corticotropin-releasing hormone
(CRHR1 gene), glucocorticoid (FKBP5 gene), and mineralocorticoid
(NR3C1 gene) receptors have all been associated with dysregulations in
the cortisol response to laboratory stress and, thus, represent targets that
may have implications for driving heightened exposure to stress (Derijk,
2009; Mahon et al., 2013; Zannas and Binder, 2014). Notably, the effects
reported in these studies appear to be stronger in individuals with a
history of childhood maltreatment, thus suggesting that the relation of
these genetic markers to future stress processes may be moderated by
distal stress exposure (Cicchetti et al., 2011; Sumner et al., 2014). Sec­
ond, markers in the oxytocin system have been targeted due to the role
of oxytocin in modulating attachment-related behaviors that may be
relevant to the generation of interpersonal stress. In particular, the
G-allele of the rs53576 SNP of the oxytocin receptor gene (OXTR) has
been associated in previous research with various pro-social outcomes,
including higher levels of empathy (Rodrigues et al., 2009) and
pro-sociality (Kogan et al., 2011). In contrast, the A (minor) allele has
been associated in these studies with negative social behaviors.
We provide the first systematic review of the molecular genetic
correlates of stress generation. We expect the studies in this area to be
heterogeneous regarding the diagnostic sample, genetic marker(s),
design (cross-sectional; prospective), and stress assessment. Therefore,
given the early state of this literature, we have chosen to conduct a
broad, systematic review of all studies on this topic instead of limiting
our focus to a homogenous subset of studies for meta-analysis. In
addition, this review pays particular attention to evaluating the meth­
odological rigor of stress assessment and its appropriateness for the
stress generation hypothesis’s specific predictions. Specifically, as
mentioned above, a crucial distinction in addressing stress generation is
between events that are dependent on, versus independent of, the in­
dividual’s agency. Relatedly, it is critical for research in this area to
assess the dependent variable (i.e., exposure to SLEs in the environment)
with a measure that is not confounded by any biases inherent in the
independent variable (e.g., genetically mediated personality traits)
(Monroe and Reid, 2008; Karg et al., 2011). That is, the question posed
in the current study, and the stress generation hypothesis in general, is
not about whether individuals with particular genetic risk perceive, or
appraise, their environments as more stressful; it is about whether these
vulnerabilities are associated with heightened exposure to actual life
events in the external environment. There is robust evidence that
A. Bahji et al.
contextual life event interviews that employ independent raters to assess
the presence and severity of SLEs provide more valid and reliable
measures of SLE exposure, unconfounded by subjective biases inherent
in the correlate of interest (e.g., genetic risk, personality, state psycho­
pathology) than self-report life event checklists.
Our overarching goal with this review is to summarize the state of
knowledge on the molecular genetic markers of stress generation to
stimulate further research bearing on this question. We hypothesize
that, in general, risk makers in the 5-HTTLPR, OXTR, and HPA axis gene
systems will be significantly associated with heightened exposure to
dependent but not independent SLEs. Further, we hypothesize that these
relations may be significantly moderated by distal stress markers, such
as a history of childhood maltreatment.
2. Methods
2.1. Protocol and registration
We followed the Preferred Reporting Items for Systematic Reviews
and Meta-analyses (PRISMA) guidelines (Liberati et al., 2009). In
addition, we registered this review using PROSPERO
(CRD42019136886).
2.2. Eligibility criteria
Eligible studies examined the relation of one or more genetic markers
to the generation of proximal SLEs. We defined a genetic marker as any
DNA sequence that causes disease or is associated with an illness
(Wikipedia, 2021). We defined proximal SLEs as stressful life events
occurring within 12 months of the life event assessment and assessed
using a validated instrument. We included studies reporting the same
sample so long as different biomarkers were considered. We excluded
studies that did not contain proximal SLEs as a primary outcome. We
also excluded studies that did not allow us to distinguish the types of
proximal SLEs central to the stress generation hypothesis. Specifically,
studies had to assess the relation of a genetic marker(s) to either (a)
independent versus dependent life events separately or (b) clearly
defined dependent events. To that end, the independent life events can
be considered the control comparison. Therefore, we excluded studies
that simply examined correlations between genetic marker(s) and an
overall index of life events, collapsing distinctions based on event in­
dependence. As the primary outcome of interest in this review was the
generation of proximal SLEs, we excluded gene-environment interaction
studies with the presence or severity of psychopathology as the outcome
(dependent) variable. Because the stress generation phenomenon has
been documented across several clinical conditions and in healthy in­
dividuals at risk for psychopathology, we did not restrict study eligibility
to particular clinical samples. We considered all study designs involving
primary data collection (e.g., case-control, longitudinal prospective,
randomized controlled trials). We excluded secondary studies, such as
review articles, commentaries, letters to the editor, editorials, and
post-hoc analyses of primary data sets. We also excluded studies without
an English-language translation.
2.3. Search strategy
After meeting with an experienced research librarian, we developed
a systematic review protocol involving six electronic databases. To
identify pertinent studies, the following ten databases were systemati­
cally searched: AMED, ProQuest, Web of Science, PubMed, MEDLINE,
PsycINFO, CINAHL, Cochrane, EMBASE, and two clinical trials regis­
tries. In addition, the following types of search terms were used: bio­
markers, neurotransmitter transport proteins, plasma membrane
neurotransmitter transport proteins, serotonin, dopamine, oxytocin,
orexins, depression, and stress generation (Appendix 1). The initial
searches were conducted in May 2019 from inception; however, a repeat
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Psychiatry Research 304 (2021) 114139
search was done on January 21, 2021. We performed backward searches
to complement this search (i.e., examining reference lists of eligible
studies).
2.4. Selection of studies
Following the removal of duplicates, two co-authors (AB and EF)
completed two independent rounds of screening (first by title and ab­
stract and then by full-text review). Most discrepancies between re­
viewers were resolved by consensus after each screening; however, a
third reviewer (KH) provided input on select articles’ suitability.
2.5. Data collection process and items
Two co-authors (AB and EF) abstracted data from included studies
and contacted study authors for data confirmation or clarification where
necessary, and we resolved disagreements by consensus. We extracted
the following data from each study: study author and title, aim, relevant
background (as per the stress generation hypothesis), study design, a
summary of the study population, investigated genetic marker, SLE
assessment, a summary of findings, and study conclusion.
2.6. Risk of bias in individual studies
We extracted sufficient data to assess study quality using the New­
castle Ottawa Scale (NOS) for cohort studies (Luchini et al., 2017; Wells
et al., 2019). The NOS uses a star system to evaluate nonrandomized
studies regarding three domains of quality (selection, comparability,
and outcome) using eight criteria: representativeness of the exposed
cohort, selection of the non-exposed cohort, ascertainment of exposure,
demonstration that the outcome of interest was not present at the start of
the study, comparability of cohorts based on the design or analysis,
assessment of outcome, sufficient length of follow-up for outcomes to
occur, and adequacy of follow-up of the cohort. For each criterion, we
assigned a star, with the sum of stars providing an overall quality score
(maximum score: 8 points). Thus, studies with 6 points or higher were of
the highest quality, studies that achieved a total rating of 3 or fewer
points were of the lowest quality, and we rated those between 4 and 5
points as fair quality. We adapted this scoring system from a previous
meta-analysis (Bahji et al., 2020b). Two co-authors (AB and EF) inde­
pendently scored studies using the NOS and resolved discrepancies by
consensus (Table 2). Note that we did not exclude studies based on their
NOS rating.
2.7. Synthesis of findings
Given the small number of studies that emerged from our review and
the very heterogeneous methods, we chose not to conduct a meta-
analysis. Instead, we synthesized study findings using descriptive ta­
bles and thematic summaries, using previously described methods
(Bahji and Stephenson, 2019; Elbatarny et al., 2019; Bahji et al., 2020a).
3. Results
3.1. Study selection
Seven studies (Starr et al., 2012, 2013; Thompson et al., 2014;
Harkness et al., 2015; Brinksma et al., 2018; Ebbert et al., 2019; Huang
and Starr, 2020) met the eligibility criteria for the systematic review
(Fig. 1).
3.2. Characteristics of studies
We provide the characteristics of all studies in Table 1. Three studies
included longitudinal designs (Brinksma et al., 2018; Starr et al., 2013,
2012) while the remaining four were cross-sectional (Thompson et al.,
A. Bahji et al.
Fig. 1. PRISMA study flow diagram.
2014; Harkness et al., 2015; Ebbert et al., 2019; Huang and Starr, 2020).
Across all seven studies, the total number of participants was 3585;
however, the participants included in Starr et al. (2012, 2013) and
Thompson et al. (2014) were drawn from the same larger sample and,
thus, were overlapping. Six studies included adolescents and young
adults, while one focused on middle adulthood (Ebbert et al., 2019).
Four of the seven studies examined the serotonin-transporter-linked
promoter region (5-HTTLPR) (Starr et al., 2012, 2013; Harkness et al.,
2015; Brinksma et al., 2018), one examined an MGPS including 10 SNPs
from four hypothalamic-pituitary-adrenal (HPA) axis genes (Huang and
Starr, 2020), and two examined the rs53576 SNP of the OXTR
(Thompson et al., 2014; Ebbert et al., 2019).
3.3. Direct tests of the stress generation hypothesis
Five studies had their explicit purpose of testing the stress generation
hypothesis (Starr et al., 2012, 2013; Harkness et al., 2015; Brinksma
et al., 2018; Huang and Starr, 2020). These five studies scored high on
the Newcastle Ottawa risk assessment instrument, indicating high
quality (Table 2). Four studies examined the 5-HTTLPR, and one
examined the MGPS. All five studies included rigorous assessments of
SLEs and analyzed the genetic marker’s relation to dependent versus
independent events separately. Specifically, four used gold-standard,
contextual interviews of life events that employed independent judges
to rate the severity and independence of events using standardized
criteria (Starr et al., 2012, 2013; Harkness et al., 2015). One used a
22-item self-report checklist; however, endorsed SLEs were subse­
quently rated for independence by a team of judges according to the
standardized criteria used in the contextual interview approach
(Brinksma et al., 2018). None of these studies showed a significant direct
correlation between the genetic marker and dependent or independent
life events. Instead, in all five studies, the genetic marker’s relation to
life events was significantly moderated by a third variable. Consistent
with the stress generation hypothesis, however, in all five studies, this
moderation relation was significant in predicting exposure to dependent
life events but was not significant in predicting exposure to independent
life events.
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Psychiatry Research 304 (2021) 114139
Brinksma et al. evaluated a sample of 1306 adolescents from the
Tracking Adolescent Individuals’ Lives Survey (TRAILS) (Brinksma
et al., 2018). They found that, among adolescents who were homozy­
gous for the S-allele of the 5-HTTLPR, elevated symptoms of
Attention-Deficit/Hyperactivity Disorder (ADHD) in middle adolescence
significantly predicted the generation of dependent-interpersonal life
events in late adolescence (β=0.20, p<0.001). However, ADHD symp­
toms did not indicate stress generation in those with the LS (β=0.03, p =
0.48) or LL genotypes (β=− 0.04, p = 0.58). Further, neither genotype
nor ADHD symptoms significantly predicted subsequent exposure to
independent life events.
Similarly, in a sample of 381 adolescents recruited from the Mater
University Study of Pregnancy who over-sampled for maternal depres­
sion, Starr et al. reported that among adolescents—who were homozy­
gous or heterozygous for the S-allele of the 5-HTTLPR—elevated
symptoms of depression at age 15 significantly predicted the generation
of dependent-interpersonal life events at age 20 (β=0.24, p <0.001)
(Starr et al., 2012). However, this association was not significant for
those with the LL genotype (β<0.001, p = 0.99). Further, neither ge­
notype nor depression symptoms significantly predicted exposure to
independent life events at age 20.
Starr et al. subsequently analyzed data from 354 adolescents
recruited from the same Mater University Study of Pregnancy (Starr
et al., 2013). They found that, among adolescents who were homozy­
gous or heterozygous for the S-allele of the 5-HTTLPR, lower levels of
relational (attachment) security at age 15 predicted higher levels of
dependent-interpersonal life events at age 20 (β=− 0.15, p = 0.046). In
direct contrast, among those with high relational security, the S-allele
presence predicted significantly lower levels of dependent-interpersonal
life events at age 20 (β=− 0.20, p = 0.008). This latter result suggests
that high attachment security served to buffer against adolescents’ ge­
netic vulnerability to generating interpersonal stress. But, again,
consistent with the stress generation hypothesis, relational security did
not predict stress generation in those with the LL genotype (β=0.13, p =
0.23). And, neither genotype nor relational security significantly pre­
dicted subsequent exposure to independent life events.
In a cross-sectional sample of 297 adolescents and young adults,
A. Bahji et al. Psychiatry Research 304 (2021) 114139

Table 1
Characteristics of included studies (n = 7).
Authors Sample Design Assessments Genetic Marker Findings

Starr et al., Secondary analysis of 381 Prospective longitudinal UCLA Life Stress Interview (Adrian and 5-HTTLPR (SS, LS, LL) Higher severity of depression
2012 adolescents from the design: age 15 to age 20 Hammen, 1993; Hammen and Brennan, symptoms at age 15 was
Mater University Study of waves 2001; Rao et al., 1999): Contextual life significantly more strongly
Pregnancy. Adolescents event interview employing independent associated with higher levels
were oversampled for judges to rate severity and of dependent-interpersonal
maternal depression independence of SLEs according to SLEs at age 20 in adolescents
(60.9% female: 95% standardized criteria homozygous or heterozygous
White) Beck Depression Inventory-II (Beck for the S-allele of the 5-
et al., 1996): 21-item self-report HTTLPR than in adolescents
measure of presence and severity of homozygous for the
depression symptoms L-allele. There was no
evidence for moderation in
predicting levels of
independent SLEs.
Starr et al., Secondary analysis of 354 Prospective longitudinal UCLA Life Stress Interview (Adrian and 5-HTTLPR (SS, LS, LL) Among adolescents
2013 adolescents from the design: age 15 to age 20 Hammen, 1993; Hammen and Brennan, homozygous or heterozygous
Mater University Study of waves 2001; Rao et al., 1999) for the S-allele of the 5-
Pregnancy. Adolescents Bartholomew Relationship HTTLPR, low relational
were oversampled for Questionnaire (Bartholomew and security at age 15 predicted
maternal depression Horowitz, 1991): Self-report rating of higher levels of dependent-
(61.3% female: 100% attachment prototypes interpersonal SLEs at age 20.
White) Still, high relational security
at age 15 predicted lower
levels of dependent-
interpersonal SLEs at age 20.
There was no evidence for
relational security to predict
dependent-interpersonal
SLEs among those
homozygous for the L-allele
of the 5-HTTLPR. Further,
there was no evidence for
moderation in predicting
levels of independent SLEs at
age 20.
Thompson Secondary analysis of 441 Cross-sectional analysis UCLA Life Stress Interview (Adrian and OXTR rs53576 Maternal history of
et al., adolescents from the at adolescent age 15 Hammen, 1993; Hammen and Brennan, (AA, AG, GG) depression significantly
2014 Mater University Study of 2001; Rao et al., 1999) predicted higher levels of
Pregnancy. Adolescents Structured Clinical Interview for chronic interpersonal stress
were over-sampled for DSM-IV Axis I Disorders (SCID) (First at youth age 15, but only for
maternal depression and Gibbon, 2004)” Structured youth homozygous or
(59.2% female: 93.7% interviews administered to mothers to heterozygous for the A-allele
White) assess the history of depression in the of OXTR.
first five years of adolescents’ life
Harkness 297 adolescents and young Cross-sectional Life Events and Difficulties Schedule-II 5-HTTLPR (SS, LS, LL) Participants homozygous or
et al., adults recruited from the (LEDS-II) (Bifulco et al., 1989; Frank heterozygous for the S-allele
2015 community (77.6% et al., 1997): Contextual life event of the 5-HTTLPR reported
female; 76% White; 50.5% interviews employ independent judges significantly higher
in a current major to rate the severity and independence of dependent-interpersonal
depressive episode) SLEs according to standardized and SLEs than those homozygous
manualized criteria. for the L-allele. However, this
Childhood Experience of Care and only occurred in those who
Abuse (CECA) interview (Bifulco et al., had maternal emotional
1994): Contextual interview of maltreatment or sexual
emotional, physical, and sexual abuse maltreatment. There was no
employing independent judges to rate evidence for an interaction of
the severity of abuse according to childhood maltreatment and
standardized and manualized criteria. genotype in the association
with levels of independent
SLEs.
Brinksma Secondary analysis of Prospective longitudinal Long-Term Difficulties Questionnaire 5-HTTLPR (SS, LS, LL) Among adolescents
et al., 1306 adolescents from the design following (LDQ) (Amone-P’Olak et al., 2009; homozygous or heterozygous
2018 Tracking Adolescents’ adolescents across three Oldehinkel et al., 2015): Self-report for the S-allele of the 5-
Individual Lives Survey time points, each two questionnaire administered to child and HTTLPR, higher severity of
(TRAILS; 50% female). years apart. Adolescents parent to assess 22 SLEs. A team of ADHD symptoms in middle
ranged in age from 10.0 independent judges subsequently rated adolescence (Time 2)
to 12.6 years at Time 1. SLEs as either “person-centered” predicted a higher number of
(dependent-interpersonal) or dependent-interpersonal
“environment-related” (independent) SLEs in late adolescence
ADHD Problems subscale of the Child (Time 3). However, there
Behavior Checklist (CBCL) (Achenbach, was no evidence for this
1991): Parent report of 7 ADHD relation among adolescents
symptoms during previous six months homozygous for the L-allele
of the 5-HTTLPR. Further,
(continued on next page)

5
A. Bahji et al. Psychiatry Research 304 (2021) 114139

Table 1 (continued )
Authors Sample Design Assessments Genetic Marker Findings

there was no evidence for

Ebbert 614 participants in midlife Cross-sectional Childhood trauma questionnaire (CTQ)
et al., (aged 40–65) recruited (Bernstein et al., 2003): Retrospective
2019 from the AS U Live Project self-report scale assessing the history of
(52% female; 71.6% emotional abuse
White) Perceived social support and strain (
Walen and Lachman, 2000): 12-item
self-report scale assessing support and
strain in the family, spouse/partner, and
friend relationships
Huang and 192 adolescents recruited Cross-sectional UCLA Life Stress Interview (Adrian and
Starr, from the community Hammen, 1993; Hammen and Brennan,
2020 (53.1% female; 100% 2001; Rao et al., 1999)
White) Youth Life Stress Interview (Rudolph
et al., 2000): Contextual interview
administered to parents to assess
“interpersonal childhood adversity.” An
independent team of judges coded
responses.
OXTR rs53576
(AA, AG, GG)
MGPS for 10 SNPs from
four HPA axis genes:
CRHR1 (rs4792887 T-
allele, rs110402 G-allele,
rs242941 T-allele,
rs242939 G-allele,
rs1876828 G-allele);
NR3C1 (rs41423247 G-
allele, rs10482605 T-allele,
rs10052957 A-allele);
NR3C2 (rs5522 G-allele);
and FKB5 (rs1360780 T-
allele)
moderation in predicting
levels of independent SLEs.
Among participants with
higher levels of emotional
abuse, those homozygous or
heterozygous for the A-allele
of OXTR reported
significantly more strain in
family relationships than
those homozygous for the G-
allele.
Higher ICA was significantly
associated with higher
dependent-interpersonal
stress among adolescents at
high MGPS but not at low
MGPS. However, this
moderation effect was not
significant for non-
interpersonal or independent
stress.

Note: ADHD = Attention Deficit/Hyperactivity Disorder; SLE=stressful life event; 5-HTTLPR: Serotonin-transporter-linked promoter region; MGPS = Multilocus
Genetic Profile Score; SNP = Single Nucleotide Polymorphism; OXTR: Oxytocin Receptor.

Table 2
Newcastle Ottawa Scale of Study Quality for Cohort Studies.
Study Representativeness Selection of Ascertainment Outcomes Comparability of Assessment Duration of Adequacy of Overall
of cohort non-exposed of exposure absent at the cohorts based on of outcome follow-up follow-up rating
cohort start of the design
study

Starr et al., * * * * * * * * High

2012 quality
Starr et al., * * * * * * * * High
2013 quality
Thompson * * * Low
et al., quality
2014
Harkness * * * * * * High
et al., quality
2015
Brinksma * * * * * * * * High
et al., quality
2018
Ebbert et al., * * * Low
2019 quality
Huang and * * * * * * High
Starr, quality
2020

Harkness et al. found that S-allele carriers of the 5-HTTLPR reported
significantly higher dependent-interpersonal events than those in the
previous three months homozygous for the L-allele (Harkness et al.,
2015). However, this was only observed among those who reported a
history of severe emotional maltreatment (β=0.22, p = 0.005).
Furthermore, this relation of genotype to dependent-interpersonal
events was not significant among those with no history of emotional
maltreatment (β=0.02, p = 0.92). Further, neither genotype nor child­
hood maltreatment, or their interaction, were associated with reports of
independent life events.
The final study included a cross-sectional sample of 192 adolescents
(Huang and Starr, 2020). This study was the only in our review to go
beyond a single genetic marker and used more sophisticated methods to
calculate a local multilocus genetic profile score. Specifically, they
created an MGPS using genotypes for 10 SNPs from four HPA axis genes:
CRHR1 (rs4792887 T-allele, rs110402 G-allele, rs242941 T-allele,
rs242939 G-allele, rs1876828 G-allele), NR3C1 (rs41423247 G-allele,
rs10482605 T-allele, rs10052957 A-allele), NR3C2 (rs5522 G-allele),
and FKB5 (rs1360780 T-allele). The authors used Pagliaccio’s (2014)
(Pagliaccio et al., 2014) established MGPS procedures. The decision to
focus on HPA axis genes was based on meta-analytic literature con­
firming HPA axis dysregulation as a strong consequence of childhood
adversity (Bernard et al., 2017). Consistent with the previous four
studies’ results, higher levels of childhood adversity are significantly
associated with higher proximal dependent-interpersonal stress levels.
However, this relation only emerged among adolescents at high MGPS
(b=0.72, p<0.001) and not among those at low MGPS (b=0.03, p =
0.89). Further, this moderation effect was not significant for
non-interpersonal or independent stress.

6
A. Bahji et al.
3.4. Indirect tests of the stress generation hypothesis
Two additional studies provided a preliminary test of the stress
generation hypothesis (Ebbert et al., 2019; Thompson et al., 2014).
Specifically, they examined dependent-interpersonal stress as an
outcome but did not provide a contrasting examination of
non-interpersonal or independent stress. Nevertheless, they are included
in this review because they tested the hypothesis that genetic risk would
predict stress exposure.
First, in a cross-sectional study of 441 15-year-old adolescents
recruited from the same Mater University Study of Pregnancy as above
(Starr et al., 2012, 2013), Thompson et al. found that those with a
maternal history of depression reported higher levels of chronic inter­
personal (i.e., relationship) stress than those without maternal depres­
sion (Thompson et al., 2014). However, this association only emerged as
significant among participants who were A-allele carriers of the OXTR
rs53576 SNP (interaction β=0.21, p<0.05). An essential strength of this
study was that chronic interpersonal stress was assessed using a rigorous
contextual interview with ’independent judges’ ratings.
Second, in a cross-sectional study of 614 participants in middle
adulthood (age 40–65), Ebert et al. examined the moderating effect of
OXTR genotype on the relation of childhood emotional abuse on strain
in adult relationships (Ebbert et al., 2019). They found a significant
moderating effect in predicting strain in family relationships but no
spouse/partner or friend relationships. Specifically, among those with a
history of emotional abuse, those with the risk A-allele reported signif­
icantly lower self-reported quality of family relationships than those
homozygous for the G-allele (statistics for the simple slopes were not
reported). However, relationship strain was assessed in this study using
a self-report questionnaire and was appropriately termed “perceived so­
cial strain.” Therefore, the authors cannot rule out the interpretation
that their effects are spurious, driven by the possibility that psycholog­
ical factors under similar genetic control bias responses on the ques­
tionnaire. Further, as noted above, neither of the above two studies
contrasted associations of the OXTR rs53576 to interpersonal stress with
associations to non-interpersonal or independent stress.
4. Discussion
The purpose of the current systematic review was to critically review
studies examining the molecular genetic markers associated with
exposure to specific environments that are at least in part dependent
upon or generated by the individual. Consistent with the stress gener­
ation hypothesis, all seven studies in the current review found evidence
for a significant relation of genetic risk to exposure to dependent
stressors, particularly in the interpersonal domain. In contrast, none of
the five studies that included both dependent-interpersonal and inde­
pendent stressors found a significant association of genetic risk to these
latter stressors independent of the individual’s agency. Importantly, in
all seven studies, there was no evidence for a direct relation of genetic
risk to dependent interpersonal stress; instead, this relation emerged
only in the context of moderation by additional psychosocial vulnera­
bilities. These moderators included elevated levels of symptoms, and
markers of a negative early environment, including a history of
emotional maltreatment, interpersonal childhood adversity (e.g., death
of, or separation from, a parent), maternal history of depression, and an
insecure attachment style.
In general, the methods employed by these studies were robust. For
example, all but one study used gold standard contextual methods for
defining and rating stressful life events that minimize reporting bias.
This is important because it strengthens conclusions that what is under
at least partial genetic control is actual exposure to, or generation of, the
stress in the environment, and not simply perceptions of, or sensitivity
to, that stress. In sum, the seven studies included in this review provide
consistent evidence that genetic risk, defined as the S-allele 5-HTTLPR,
the A-allele of the OXTR, or multilocus risk in HPA axis genes,
7
Psychiatry Research 304 (2021) 114139
significantly raises the risk for the generation of acute and chronic
proximal stress in individuals’ interpersonal relationships in the context
of additional psychosocial vulnerability.
Findings emerged most strongly for the 5-HTTLPR. All four studies
investigating this marker differentiated relations to dependent-
interpersonal versus independent stress with contextual stress assess­
ment methods. Further, in two of these studies, the moderator variables
were also assessed with rigorous independent interviews, and three
studies included rigorous prospective designs. Several complementary
mechanisms have been theorized to mediate the relation of the 5-
HTTLPR polymorphism and stress generation, particularly in the
context of elevated levels of symptoms and/or early psychosocial
vulnerability. For example, the 5-HTTLPR polymorphism of the sero­
tonin transporter gene has been theorized to mediate an amygdala-
anterior cingulate-cortical circuit that underlies rumination (Pezawas
et al., 2005). In addition, rumination is a common pathological feature
of depression (Olatunji et al., 2013), a robust prospective predictor of
dependent-interpersonal stress exposure (McLaughlin and Nolen-Hoek­
sema, 2012), and elevated among youth with a history of emotional
maltreatment and/or maternal history of depression (Woody et al.,
2016). In particular, Antypa and Van der Does report that young adults
with a history of emotional maltreatment had higher levels of rumina­
tion than those without, but only among S-allele carriers of the
5-HTTLPR (Antypa et al., 2010). Therefore, perhaps youth with elevated
symptoms or early vulnerability are only likely to generate stress in their
interpersonal relationships if they are also at risk of ruminating on these
vulnerabilities’ causes and consequences.
The stress generation hypothesis also suggests that maladaptive
personality characteristics and negative interpersonal behaviors drive
the generation of conflict and tension in interpersonal relationships.
Furthermore, there is evidence that the sorts of personality traits that
underlie negative interpersonal behaviors, such as high levels of
Neuroticism, are under genetic control by the 5-HTTLPR polymorphism
of the serotonin transporter gene (Schinka et al., 2004). However, future
research is needed to develop an integrated model for understanding
how genetic risk and early psychosocial vulnerability are translated
behaviorally into the generation of dependent interpersonal stress.
Similar results to the above were found in the one study examining
an MGPS of HPA axis genes. Conclusions regarding the role of HPA axis
genes in stress generation should be considered preliminary given the
evidence space consists of just this one study. Nevertheless, the methods
of this study were strong. First, it used rigorous contextual interviews of
both proximal life event exposure and the moderator, childhood
adversity. Second, instead of relying on a single genetic marker, it
created an MGPS based on established procedures. The MGPS approach
has been found to have greater predictive validity than examining single
SNPs because the multiple SNPs are selected theoretically to capture the
cumulative, polygenic effects of a specific biological system (Pagliaccio
et al., 2014). The MGPS investigated by Huang and Starr has been shown
to predict neuroendocrine, limbic, and affective reactivity to stress.
Therefore, future research is required to determine whether these
genetically linked mechanisms in the HPA axis system also drive the
generation of stress in those with a strong history of early adversity.
Conclusions regarding the OXTR rs53576 should also be considered
preliminary. First, neither of the two studies investigating this poly­
morphism contrasted the generation of dependent-interpersonal stress
with independent stress. Further, these studies provided proxy measures
for stress exposure and, in one, relying on subjective perceptions of
interpersonal relationship strain. Therefore, the results of these studies
should be replicated using more rigorous contextual interviews and
rating measures. Nevertheless, these studies’ findings suggest that
negative early experiences predict later interpersonal stress more
strongly in those at genetic risk for lower social competence. As noted
above, the A-allele of the OXTR rs53576 has been associated with lower
levels of trust, less accurate and empathic processing of social infor­
mation, and less secure attachment. Therefore, it may be challenging for
A. Bahji et al.
A-allele carriers who grow up with a depressed mother or suffer
emotional abuse to develop social competencies necessary for promot­
ing healthy interpersonal functioning later in life. Future research is
needed to identify the specific interpersonal processes affected by OXTR
in the generation of stress.
4.1. Limitations and directions for future research
The current review is limited by the design features of the reviewed
studies. First, one study did not employ a gold standard contextual
interview. It thus cannot rule out depressive or other biases in driving
the relationship of genetic risk to stress generation. Several authors have
emphasized how important it is in genetic studies to use environmental
measures that do not confound stress exposure with the stress response
(Karg et al., 2011; Monroe and Reid, 2008). Second, all but one of the
included studies focused on adolescent participants, and ethnic and
socioeconomic diversity were limited. Third, it is important to note that
three of the studies reviewed here included the same sample of partic­
ipants, with minor variations in sample size based on inclusion criteria
for each publication’s specific analysis. Therefore, the results reported in
this systematic review may be inflated, and more replication in inde­
pendently collected samples is required. Finally, the psychosocial
moderators across studies, including early adverse events, maternal
depression, and attachment style, were diverse and suggested poten­
tially unique mechanisms. Therefore, there is a need for future research
to determine how each of these moderators uniquely relate to stress
generation and, as such, whether they might prove differentially
modifiable through intervention
The stress generation hypothesis offers exciting insights into the
pathophysiology of depression. This review focused on genetics as one
potential contribution to the stress generation hypothesis of depression,
but this is a very open study area with many questions left to be
explored. For example, future studies should expand to include addi­
tional genetic markers in neural systems associated with stress, such as
Brain-Derived Neurotrophic Factor (BDNF) genes (Aso et al., 2008;
Aguilera et al., 2009; Toyokawa et al., 2012). BDNF is critical for pro­
moting neurogenesis, and decreased synthesis of BDNF in the context of
risk polymorphisms of the BDNF gene have been associated with
Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.psychres.2021.114139.
Appendix 1. Search syntaxes
AMED (Allied and Complementary Medicine): 1985 to January 21, 2021
# Searches
1 Stress generation.mp
2 Life events.mp
3 Depress*
4 1 or 2
5 3 and 4
Cochrane Central Register of Controlled Trials: inception to January 21, 2021
# Searches
1 Stress generation. mp
2 Life events. mp
3 Depress*
4 1 or 2
5 4 and 5
8
Psychiatry Research 304 (2021) 114139
hippocampal atrophy and reduced telomere length following stress
(Aguilera et al., 2009; Aso et al., 2008). The field also requires more
studies using sophisticated genetic marker assessment, including
creating MGPS or haplotypes or applying GWAS methods. These meth­
odologies have been successfully employed in gene-by-environment
interaction studies predicting psychopathology (Arnau-Soler et al.,
2019; Feurer et al., 2017) and could be easily applied to
gene-environment correlation (stress generation) designs. Also, there is
solid and compelling evidence that early vulnerabilities, including a
maternal history of depression and exposure to childhood abuse, induce
epigenetic changes (Yehuda and Lehrner, 2018). These epigenetic
changes have been shown to underlie, at least in part, the intergenera­
tional transmission of depression (Sawyer et al., 2019). An intriguing
hypothesis for future research is that interpersonal stress generation
may mediate this relation. Finally, future research at neurobiological,
cognitive-emotional, and behavioral levels of analysis is now required to
elucidate the mechanisms that translate genotype into behavior to
develop interventions that can remediate maladaptive interpersonal
functioning among those at the highest risk.
5. Conclusions
The current systematic review is the first to integrate and critically
evaluate the literature on the relation of molecular genetic markers to
the generation of SLEs. Compared with the body of literature examining
gene-by-environment interaction in predicting psychopathology, the
gene-stress generation literature is in its infancy. Only seven studies
were identified that examined the relation of genetic markers to SLEs
relevant to stress generation (i.e., SLEs at least in part dependent on the
individual’s agency). All seven of these studies were consistent in
finding no evidence for a direct relation of genotype to dependent SLEs.
Instead, in all studies, the effect of genotype on stress generation was
moderated by the additional vulnerability. However, consistent with the
stress generation hypothesis, these moderation effects significantly
predicted exposure to dependent- interpersonal stress but not indepen­
dent stress. Therefore, these encouraging preliminary results support
early behavioral genetics findings showing that exposure to the envi­
ronment is partly under genetic control.
Results
5
196
7940
201
54
Results
0
4
95,268
4
1
A. Bahji et al. Psychiatry Research 304 (2021) 114139

OVID Embase: 1947 to January 21, 2021

# Searches Results
1 Stress generation. mp 604
2 Depress* 776,142
3 1 and 2 116
OVID MEDLINE (R): 1946 to January 21, 2021
# Searches Results
1 Stress generation.mp 563
2 Depress* 510,734
3 1 and 2 102

OVID PsycINFO: 1806 to January 21, 2021

# Searches Results
1 Stress generation. mp 236
2 Depress* 336,734
3 1 and 2 186

PubMed: inception to January 21, 2021

# Searches Results
1 “Stress generation,” 547
2 Depress* 512,101
3 1 and 2 102

Web of Science Core Collection: inception to January 21, 2021

# Searches Results
1 “Stress generation,” 1626
2 Depress* 579,397
3 1 and 2 288

CINAHL: inception to January 21, 2021

# Searches Results
1 “Stress generation,” 326
2 Depress* 154,683
3 1 and 2 71

International Clinical Trials Registry Platform: inception to January 21, 2021

# Searches Results
1 “Stress generation,” and depression 0

ProQuest Dissertations and Theses Global: inception to January 21, 2021

# Searches Results
1 “Stress generation” and “depression” 1127

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